Reperfusion of the previously ischemic intestine leads to a devastating local injury, with mucosal necrosis and remote injury exemplified by a rise in hepatocellular enzymes and lung permeability edema. The local injury is largely mediated by deposition of IgM which activates the classical pathway of complement. Ultimately the complex, C5b-9 is deposited on the mucosa. Remote injury is neutrophil (PMN) mediated. Our focus is on the role of complement since if we can moderate local injury, remote organ damage is minimized. Further, complement fragment, iC3b participates in remote injury by ligating PMN CR3 (CD11b) and activating the cell. In projected experiments, we will test whether the adhesion molecule, P-selectin also function as a complement regulatory protein. Evidence indicates that one or more of its 9 short consensus repeats regulate classical pathway complement activity and that genetic deficiency of P-selectin remote reperfusion injury. Experiments have been designed to examine: 1) in vitro ability of soluble(s)P-selectin or thrombin activated platelets expressing P-selectin to inhibit complement lytic activity; 2) resistance of transgenic mice, overexpressing the extramembranous sections of P-selectin (high levels of sP-selectin), to jejunal ischemia injury; 3) complement (C3) transport function of PMNs to regions remote from the reperfused jejunum; 4) ability of platelets expressing P-selectin to limit remote injury by competing with PMN for C3. In other experiments we will test the importance of IgM in classical complement activation: 1) sequence of IgM and C1q binding to reperfused jejunum; 2) source of IgM, circulating or bound to peritoneal B cells; 3) role of the natural antibody fraction of IgM; 4) reexamine the role of the alternative pathway of complement. Finally, anti-complementary fusion molecules which bind to P-selectin, expressed in areas of injury will be tested as therapy to moderate injury without systemically inhibiting complement.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM052585-08
Application #
6587653
Study Section
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
8
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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